Alzheimer's disease (AD) is the most common dementia, resulting in devastating declines in cognition, quality of life, and financial burden to society. Unfortunately, the prevalence of Alzheimer's disease and the associated costs are predicted to dramatically increase in the future, due to shifts in life expectancy and demographics. Current treatments with cholinesterase inhibitors provide only modest symptomatic relief to a proportion of patients and do not alter disease progression. It has been well established in animal studies that nerve growth factor (NGF) delivery to the brain can prevent the death of and reverse the decline of the [unreadable] same cholinergic neurons associated with the cognitive decline in aging and AD. However, attempts to apply these data to clinical patients by application of intracerebroventricular (ICV) NGF protein infusion resulted in significant adverse effects of weight loss and back pain, due to NGF effects in non-target regions of the CNS. [unreadable] Thus, a means of precisely, selectively, and chronically delivering NGF to degenerating basal forebrain [unreadable] cholinergic neurons in Alzheimer's brains are required. Gene therapy potentially offers such a means. In vivo gene therapy, where vectors are directly injected into the brain, is the most feasible approach for wide-scale commercialization of gene delivery to the central nervous system (CNS). Ceregene Inc. is pursuing commercialization of in vivo gene therapy to deliver NGF to degenerating cholinergic neurons in the nucleus basalis of Meynert (NBM) in patients with Alzheimer's disease. Studies completed in our SBIR Phase I grant period resulted in the design and selection of our lead clinical vector, CERE-110, a replication incompetent genetically engineered adeno-associated virus carrying the human NGF transgene. In our SBIR Phase II grant period, we aim to complete preclinical pharmacology and toxicology/safety studies of CERE-110 in rats and monkeys and file an IND for a Phase 1/11clinical study of CERE-110 in patients with mild Alzheimer's disease. Successful clinical trials would result in the commercialization of CERE-110 as a therapeutic agent for patients with Alzheimer's disease, providing for the first time a means of reducing actual cell loss in any human neurological disorder. [unreadable] [unreadable] [unreadable]